Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE
Interdisciplinary Graduate Program
Department of Medicine, Division of Infectious Diseases and Immunology
Medical Subject Headings
Animals; Antigen-Antibody Complex; Antigens, Neoplasm; B-Lymphocytes; CpG Islands; DNA-Binding Proteins; Dendritic Cells; HMGB1 Protein; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Oligodeoxyribonucleotides; Receptors, Cell Surface; Toll-Like Receptor 9
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.
Rights and Permissions
Citation: Nature Immunology 8, 487 - 496 (2007). doi:10.1038/ni1457
Tian, Jane; Avalos, Ana Maria; Mao, Su-Yau; Chen, Bo; Senthil, Kannaki; Wu, Herren; Parroche, Peggy; Drabic, Stacey; Golenbock, Douglas T.; Sirois, Cherilyn M.; Hua, Jing; An, Ling Ling; Audoly, Laurent; La Rosa, Greg; Bierhaus, Angelika; Naworth, Peter; Marshak-Rothstein, Ann; Crow, Mary K.; Fitzgerald, Katherine A.; Latz, Eicke; Kiener, Peter A.; and Coyle, Anthony J., "Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE" (2007). GSBS Student Publications. Paper 1652.